Preparation of antigen-presenting human γδ T cells and use in immunotherapy

Abstract

Cytotoxic αβ T cells form an essential component in immunity to infections and tumors, and are also implicated in host defense against these challenges. The present disclosure demonstrates the ability of activated γδ T cells to cross-present exogenous antigens to CD8+αβ T cells, a process previously thought to be mediated best by dendritic cells. In particular, the present disclosure provides a method for cross-presentation of antigen derived from tumor cell or microbial organisms such as viruses, bacteria, yeasts, parasites, and the like, or from cells infected with such organisms, to a CD8+αβ T cell. Still further, the present disclosure provides a method for treatment of a tumor or a chronic or recurrent infectious disease, comprising delivering an antigen-presenting autologous γδ T cell population above into a patient requiring such treatment. Still yet further, a method is described for preparing a peptide-specific effector T cell.

Description

[0001]This application is a continuation-in-part of U.S. patent application Ser. No. 11 / 573,912, filed on Feb. 19, 2007, now U.S. Pat. No. 8,153,426 which in turn is a national stage application of International Patent Application No. PCT / CH05 / 00469, filed on Aug. 11, 2005, the entirety of the disclosures of each of which are incorporated herein by reference.TECHNICAL FIELD[0002]The invention relates to a method for the preparation of efficient antigen-presenting human γδ T cells, to the γδ T cells prepared by such a method, and to their use in immunotherapy, antigen identification and diagnosis of immune competence. In particular, the invention relates to cross-presentation of tumor-, bacterial-, or virus-derived antigens to human CD8+αβ T cells.BACKGROUND OF THE INVENTION[0003]The Cellular Components of the Adaptive Immune System[0004]The cellular components of the immune system are divided into the cells of the innate immune system and the cells of the adaptive (acquired or speci...

AI Technical Summary

Benefits of technology

[0025]The present invention describes the simple isolation and in vitro preparation of antigen-presenting human γδ T cells and their use as efficient antigen-presenting cells (APCs) in immunotherapy. Similar to dendritic cells (DCs) in potency and efficacy, human γδ T cells process antigens and present antigenic peptides to αβ T cells and induce antigen-specific responses (proliferation and differentiation) in naïve αβ T cells. γδ T cells are relative frequent in peripheral blood (2-10% of CD3+ T cells), are easily purified from peripheral blood by diverse simple techniques, acquire “maturation” status (expression of MHC-II, and essential adhesion and co-stimulatory molecules) within 1 day of in vitro culture under simple stimulatory conditions, maintain efficient antigen-presenting functions over 7 days or more of in vitro culture and induce strong primary and secondary T helper cell responses. Furthermore, γδ T cells are readily expanded during in vitro culture for storage and later use.

Problems solved by technology

Importantly, none of these findings support a role for γδ T cells in antigen presentation.

However, this role is not further defined and there is no evidence that γδ T cells may function as antigen-presenting cells.

They themselves are poorly immunogenic, i.e. are not capable of inducing primary adaptive immune responses.

Effector T cells home to sites of inflammation, rapidly mount effector functions (cytokine secretion, lysis / killing of infected / tumor cells) and have a limited life-span.

Currently, the application of DCs in immunotherapy faces several problems (Fong and Engleman, 2000; Steinman et al., 2003; Schuler et al., 2003: Figdor et al., 2004).

DCs are functionally heterogeneous and may induce opposing or unwanted effects, e.g. immune suppression instead of effector T cell generation.

This causes great difficulties in generating functionally homogeneous DC preparations by in vitro manipulations.

Finally, the generation of peptide-presenting DCs for use in immunotherapy is technically demanding, time consuming and costly.

Images